Management of radiological causalities that could occur from natural calamities, failures in operational safety mechanisms of nuclear power plants, or even a terrorist attack require immediate intervention from emergency responders and medical personnel. The damage caused by a meltdown can be catastrophic as it could release large amounts of radiation that quickly affects the environment and the health of surrounding population. Recent events involving the Fukushima Daiichi nuclear reactor have shown the unfortunate and immediate dangers posed by accidental radiation exposure. Nuclear exposure management protocols include rapid dose assessment for the affected population and identification of the individuals who require immediate medical attention. Development of robust biomarkers based on an individual's biological response is crucial for accurate assessment of the level of exposure and making important medical decisions. A personalized assessment will allow evaluation of an individual's physiological response to radiation damage. The calculated LD50 for humans exposed to total body irradiation is in the range of 4.0 to 4.5 Gy and the dose range at which supportive care will be effective is narrow. Therefore, development of biomarkers for fast and accurate dose assessment is critical. Moreover, an individual's response varies depending on many confounding factors, such as immune status, age and genetics. These factors will ultimately determine a person's apparent response to exposure, and in some cases victims may not immediately exhibit visible signs of radiation damage. Therefore, physical dosimetry alone, and the available protein markers such as cytokines, have limitations to accurately estimate the dose and response of an individual.
Acute effects (Acute Radiation Syndromes, ARS) manifest themselves as Hematopoietic, Gastrointestinal (GI), and Cerebrovascular syndromes. Studies have shown that individuals exposed to an intermediate dose (5-8 Gy) could die within a few weeks due to GI syndrome. Lower doses (2-5 Gy) that are not immediately lethal but compromise the hematopoietic system can increase susceptibility to infection and death within months if supportive care is not provided in time [Waselenko J K, et al. (2004) Ann Intern Med 140:1037-1051; MacNaughton W K (2000) Aliment Pharmacol Ther 14: 523-528; Hall E J, et al. (2012) Radiobiology for the Radiologist. Seventh Edition: 193-200; Singh V K, et al. (2009) Exp Hematol 38: 61-70; Hanson W R, et al. (1984) Radiat Res 100: 290-297; Shimizu Y, et al. (2010) BMJ 340: b5349]. In addition, several of the victims who show little or no signs of acute radiation sickness could find themselves dealing with late effects in the form of cancer, pulmonary fibrosis, and chronic or progressive heart and kidney diseases. Epidemiological studies on survivors of the Hiroshima and Nagasaki A-bombs and Chernobyl nuclear accident showed an increased incidence of various cancers and cardiovascular diseases [Shimizu Y, et al. (2010) BMJ 340: b5349; Preston D L, et al. (2003) Radiat Res 160: 381-407]. Thus, development of biomarkers capable of accurately estimating the dose absorbed is important for identifying the individuals at risk for acute as well as late effects. Understanding the dose exposed can help in the making of medical decisions and timely administration of immune-modulators and mitigators. Development of such biomarkers can also help understand the response and toxicity in patients receiving therapeutic radiation, particularly for those who receive total body irradiation as a preparative step for bone marrow transplantation.
Over the last several years, there have been attempts to estimate the radiation dose exposed using hematological, biochemical, and cytogenetic parameters [Blakely W F, et al. (2010) Health Phys 99 Suppl 5: S184-191; Ossetrova N I, et al. (2010) Health Phys 98:204-208; Blakely W F, et al. (2010) Health Phys 98: 153-159]. Several protein markers such as C-reactive protein, amylase, and cytokines, such as transforming growth factors, have been investigated for their potential as biodosimeters [Blakely W F, et al. (2010) Health Phys 98: 153-159]. These protein markers, however, have large inter-individual variations; the readouts are indirect and fluctuate as a result of common variables such as inflammation and infection [Blakely W F, et al. (2010) Health Phys 99 Suppl 5: S184-191; Blakely W F, et al. (2010) Health Phys 98: 153-159]. Currently, lymphocyte depletion kinetics, clinical observation, and the dicentric chromosome (DC) assay are used for post exposure dose assessment. Lymphocyte depletion analysis requires repeated measurements over a prolonged period of time and the DC assay is highly technically involved and labor intensive [Blakely W F, et al. (2010) Health Phys 99 Suppl 5: S184-191; Chng W J, et al. (2004) Clin Diagn Lab Immunol 11: 168-173]. Therefore, there are needs for identification of biomarkers that are sensitive to incremental changes in dose, are robust and stable for days after exposure, and repeatedly assayable in a non-invasive or minimally invasive manner.